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These recommendations involve no substantial changes to the recommended approach for rabies postexposure or
pre-exposure prophylaxis. ACIP recommends that prophylaxis for the prevention of rabies in humans exposed to rabies virus should
include prompt and thorough wound cleansing followed by passive rabies immunization with human rabies immune globulin
(HRIG) and vaccination with a cell culture rabies vaccine. For persons who have never been vaccinated against rabies,
postexposure antirabies vaccination should always include administration of both passive antibody (HRIG) and vaccine (human diploid
cell vaccine [HDCV] or purified chick embryo cell vaccine [PCECV]). Persons who have ever previously received complete
vaccination regimens (pre-exposure or postexposure) with a cell culture vaccine or persons who have been vaccinated with other types
of vaccines and have previously had a documented rabies virus neutralizing antibody titer should receive only 2 doses of
vaccine: one on day 0 (as soon as the exposure is recognized and administration of vaccine can be arranged) and the second on day
3. HRIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously unvaccinated persons to
provide immediate, passive, rabies virus neutralizing antibody coverage until the patient responds to HDCV or PCECV by
actively producing antibodies. A regimen of 5 1-mL doses of HDCV or PCECV should be administered intramuscularly to
previously unvaccinated persons. The first dose of the 5-dose course should be administered as soon as possible after exposure (day
0). Additional doses should then be administered on days 3, 7, 14, and 28 after the first vaccination. Rabies pre-exposure
vaccination should include three 1.0-mL injections of HDCV or PCECV administered intramuscularly (one injection per day on
days 0, 7, and 21 or 28).

Modifications were made to the language of the guidelines to clarify the recommendations and better specify the situations
in which rabies post- and pre-exposure prophylaxis should be administered. No new rabies biologics are presented, and no
changes were made to the vaccination schedules. However, rabies vaccine adsorbed (RVA, Bioport Corporation) is no longer available
for rabies postexposure or pre-exposure prophylaxis, and intradermal pre-exposure prophylaxis is no longer recommended because
it is not available in the United States.

Introduction

Rabies is a zoonotic disease caused by RNA viruses in the Family
Rhabdoviridae, Genus Lyssavirus
(1--4). Virus is typically present in the saliva of clinically ill mammals and is transmitted through a bite. After entering the central nervous system of
the next host, the virus causes an acute, progressive
encephalomyelitis that is almost always fatal. The incubation period in
humans is usually several weeks to months, but ranges from days to years.

As a result of improved canine vaccination programs and stray animal control, a marked decrease in domestic animal
rabies cases in the United States occurred after World War II. This decline led to a substantial decrease in indigenously
acquired rabies among humans (5). In 1946, a total of 8,384 indigenous rabies cases were reported among dogs and 33 cases in humans.
In 2006, a total of 79 cases of rabies were reported in domestic dogs, none of which was attributed to enzootic dog-to-dog
transmission, and three cases were reported in humans
(6). The infectious sources of the 79 cases in dogs were wildlife reservoirs or
dogs that were translocated from localities where canine rabies virus variants still circulate. None of the 2006 human rabies cases
was acquired from indigenous domestic animals
(6). Thus, the likelihood of human exposure to a rabid domestic animal in
the United States has decreased substantially. However, one of the three human rabies cases diagnosed in 2006 was associated
with a dog bite that occurred in the Philippines, where canine rabies is enzootic. The risk for reintroduction from abroad remains
(7). International travelers to areas where canine
rabies remains enzootic are at risk for exposure to rabies from domestic and
feral dogs.

Unlike the situation in developing countries, wild animals are the most important potential source of infection for
both humans and domestic animals in the United States. Most
reported cases of rabies occur among carnivores, primarily
raccoons, skunks, and foxes and various species of bats.
Rabies among insectivorous bats occurs throughout the continental United
States. Hawaii remains consistently rabies-free. For the past several decades, the majority of naturally acquired, indigenous
human rabies cases in the United States have resulted
from variants of rabies viruses associated with insectivorous bats
(5). The lone human case reported in the United States during 2005 and two of the three human rabies cases in 2006 were attributed to
bat exposures (6,8). During 2004, two of the eight human rabies cases resulted from bat exposures. One of these rabies
patients recovered and remains the only rabies patient to have survived without the administration of rabies vaccination
(9). Rabies was not immediately recognized as the cause of death in the other 2004 patient, and organs and a vascular graft from this patient
were transplanted into four persons, resulting in clinical rabies and death in all of the recipients
(10).

Approximately 16,000--39,000 persons come in contact with potentially rabid animals and receive rabies postexposure
prophylaxis each year (11). To appropriately manage potential human exposures to rabies, the risk for infection must be
accurately assessed. Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency, but decisions
must not be delayed. Prophylaxis is occasionally complicated by adverse reactions, but these reactions are rarely severe
(12--16).

For these recommendations, data on the safety and efficacy of active and passive rabies vaccination were derived from
both human and animal studies. Because controlled human trials cannot be performed, studies describing extensive field
experience and immunogenicity studies from certain areas of the world were reviewed. These studies indicated that postexposure
prophylaxis combining wound treatment, local infiltration of rabies immune globulin (RIG), and vaccination is uniformly
effective when appropriately administered
(17--22). However, rabies has occasionally developed among humans when key elements of
the rabies postexposure prophylaxis regimens were omitted or incorrectly administered. Timely and appropriate human
pre-exposure and postexposure prophylaxis will prevent
human rabies; however, the number of persons receiving prophylaxis can
be reduced if other basic public health and veterinary programs are working to prevent and control rabies. Practical and
accurate health education about rabies, domestic animal vaccination and responsible pet care, modern stray animal control, and
prompt diagnosis can minimize unnecessary animal exposures, alleviate inherent natural risks after exposure, and prevent many
circumstances that result in the need for rabies prophylaxis.

Methods

The Advisory Committee on Immunization Practices (ACIP) Rabies Workgroup first met in July 2005 to review
previous ACIP recommendations on the prevention of
human rabies (published in 1999) and to outline a plan for updating and
revising the recommendations to provide clearer, more specific guidance for the administration of rabies pre-exposure and
postexposure prophylaxis. The workgroup held monthly teleconferences to discuss their review of published and unpublished data on
rabies
and related biologic products. Data on the effectiveness, efficacy, immunogenicity, and safety of rabies biologics in both
human and animal studies were reviewed using a systematic, evidence-based approach.

Randomized trials or well-conducted cohort studies with untreated comparison groups would provide the best evidence of
the direct effectiveness of rabies pre-exposure and postexposure prophylaxis to prevent rabies-associated death. However, because
of the almost universal fatality among untreated persons infected with rabies virus, no such controlled studies exist.
However, studies describing final health outcomes among persons exposed to the rabies virus do exist, including studies using
formulations of rabies biologics, timing of vaccine doses, and routes of administration that are not recommended for use in the
United States. These and other studies were identified by reviewing the PubMed
database and relevant bibliographies and by
consulting subject-matter experts. The literature review did not identify any studies of the direct effectiveness of rabies pre-exposure
vaccination in preventing human rabies cases. Such studies would be difficult to conduct because rabies pre-exposure vaccination
is intended to simplify the postexposure prophylaxis that is required after a recognized rabies exposure. Rabies
pre-exposure vaccination also might afford immunity
against an unrecognized rabies exposure, an outcome that would be difficult
to measure in controlled studies. However, rabies cases have occurred among those who received rabies pre-exposure
prophylaxis and did not receive rabies postexposure prophylaxis
(23), indicating that pre-exposure prophylaxis in humans is not
universally effective without postexposure prophylaxis. Because of the paucity of formal studies on the effectiveness of rabies
pre-exposure vaccination in humans, the literature was searched for studies that reported clinical outcomes among animals that received
pre-exposure rabies prophylaxis with cell culture rabies vaccine and were subsequently challenged with rabies virus. Evaluation of
the effectiveness of antirabies biologics in experimental animal models has been essential to developing successful
rabies prevention approaches for exposed humans. Animal studies investigating the effectiveness of both pre-exposure and posteexposure
rabies prophylaxis were reviewed and were used to make inferences about the direct effectiveness of
licensed rabies biologics in preventing human rabies.

Data regarding the immunogenicity of rabies biologics also were reviewed. Assessing protective immunity against rabies
is complex. Virus neutralizing antibodies are believed to have a primary role in preventing rabies virus infection. However,
antibody titers alone do not always directly correlate with absolute protection because of other important
immunologic factors. Nonetheless, the ability of a vaccine to elicit rabies virus neutralizing antibodies in animals and humans and the
demonstration of protection in animals is generally viewed as a reasonable surrogate of protection for inferential extension to
humans (24). Although a definitive "protective" titer cannot be described for all hosts under all exposure scenarios, two working
definitions of adequate rabies virus neutralizing antibody reference values have been developed to define an appropriate,
intact adaptive host response to vaccination. The literature review included studies in
humans that measured rabies virus neutralizing antibody in response to rabies postexposure prophylaxis consisting of human
rabies immune globulin (HRIG) and 5 intramuscular (IM) doses of cell culture rabies vaccine and the recommended pre-exposure prophylaxis regimen of 3 IM doses of
cell culture vaccine. The outcomes of interest for these studies were antibody titers of 0.5 IU/mL (used by the World Health
Organization [WHO] as an indicator of an adequate adaptive immune response)
(25) or complete virus neutralization at a 1:5
serum dilution by the rapid fluorescent focus inhibition test (RFFIT) (used by ACIP as an indicator of an adequate adaptive
immune response) (26). The literature also was searched for evidence regarding the safety of the licensed
rabies biologics available for use in the United States in both pre-exposure and postexposure situations.

ACIP's charter requires the committee to consider the costs and benefits of potential recommendations when they
are deliberating recommendations for vaccine use in the United States. Few studies exist on the cost-effectiveness of rabies
prophylaxis in various potential exposure scenarios. A challenge in conducting such studies is the lack of data on the probability
of rabies transmission under different exposure scenarios, except when the involved animal tests positive for rabies. To
provide information on the cost-effectiveness of rabies postexposure prophylaxis, a new analysis was conducted to estimate the
cost-effectiveness of rabies postexposure prophylaxis in various potential exposure scenarios. A Delphi methodology was used
to estimate the risk for transmission of rabies to a
human in each of the scenarios, and this information was used in the
cost-effectiveness calculations.

The rabies workgroup reviewed the previous ACIP recommendations on the prevention of human rabies and deliberated
on the available evidence. When definitive research evidence was lacking, the recommendations incorporated
expert opinion of the workgroup members. The workgroup sought input from members of the National Association of State Public Health
Veterinarians, the Council of State and Territorial Epidemiologists (CSTE), and state and local public health officials. The
proposed revised recommendations and a draft statement were presented to ACIP in October 2006. After deliberations, the
recommenda
tions were unanimously approved with minor modifications. Further modifications to the draft statement were made
following the CDC and external review process to update and clarify wording in the document.

Rabies Biologics

Three cell culture rabies vaccines are licensed in the United States: human diploid cell vaccine (HDCV,
Imovax® Rabies, sanofi pasteur), purified chick embryo cell vaccine (PCECV,
RabAvert®, Novartis Vaccines and Diagnostics), and rabies
vaccine adsorbed (RVA, Bioport Corporation). Only HDCV and PCECV are available for use in the United States (Table 1). For
each of the available vaccines, the potency of 1 dose is greater than or equal to the WHO-recommended standard of 2.5
international units (IU) per 1.0 mL of vaccine
(27). A full 1.0-mL IM dose is used for both
pre-exposure and postexposure prophylaxis regimens. Rabies vaccines induce an active immune response that includes the production of virus neutralizing antibodies.
The active antibody response requires approximately 7--10 days to develop, and detectable rabies virus neutralizing antibodies
generally persist for several years. A vaccination series is initiated and completed usually with one vaccine product. No clinical
trials were identified that document a change in efficacy or the frequency of
adverse reactions when the series is initiated with
one vaccine product and completed with another.

The passive administration of RIG is intended to provide an immediate supply of virus neutralizing antibodies to bridge
the gap until the production of active immunity in response to vaccine administration. Use of RIG provides a rapid, passive
immunity that persists for a short time (half-life of approximately 21 days)
(28). Two antirabies immune globulin (IgG)
formulations prepared from hyperimmunized human donors are licensed and available for use in the United States:
HyperRab S/D (Talecris Biotherapeutics) and
Imogam® Rabies-HT (sanofi pasteur). In all postexposure prophylaxis regimens, except for persons
previously vaccinated, HRIG should be administered concurrently with the first dose of vaccine.

Vaccines Licensed for Use in the United States

Human Diploid Cell Vaccine

HDCV is prepared from the Pitman-Moore strain of
rabies virus grown on MRC-5 human diploid cell culture,
concentrated by ultrafiltration, and inactivated with beta-propiolactone
(22). HDCV is formulated for IM administration in a single-dose
vial containing lyophilized vaccine that is reconstituted in the vial with the accompanying sterile diluent to a final volume of 1.0
mL just before administration. One dose of reconstituted vaccine contains
<150 µg neomycin sulfate, <100 mg albumin, and 20
µg of phenol red indicator. It contains no preservative or stabilizer.

Purified Chick Embryo Cell Vaccine

PCECV became available in the United States in 1997. The vaccine is prepared from the fixed rabies virus strain Flury
LEP grown in primary cultures of chicken fibroblasts
(29). The virus is inactivated with betapropiolactone and further processed
by zonal centrifugation in a sucrose density gradient. It is formulated for IM administration in a single-dose vial containing
lyophilized vaccine that is reconstituted in the vial with the accompanying sterile diluent to a final volume of 1.0 mL just
before administration. One dose of reconstituted vaccine contains <12 mg polygeline, <0.3 mg human serum albumin, 1 mg
potassium glutamate, and 0.3 mg sodium EDTA. No preservatives are added.

Rabies Immune Globulins Licensed for Use in the United States

The two HRIG products,
HyperRab S/D and
Imogam® Rabies-HT, are IgG preparations concentrated by cold
ethanol fractionation from plasma of hyperimmunized human donors. The
HyperRab S/D is formulated through the treatment of
the immune globulin fraction with 0.3% tri-n-butyl phosphate (a solvent to inactivate potential adventitious
viruses) and 0.2% sodium cholate (a detergent to inactivate potential adventitious viruses) and the application of heat (30°C [86°F] for 6
hours). After ultrafiltration, the final product is a 15%--18% protein solution in glycine. The
Imogam® Rabies-HT is prepared from
the cold ethanol fraction of pooled venous plasma of donors, stabilized with glycine, and subjected to a heat-treatment
process (58°C--60°C [136°F--140°F] for 10 hours) to inactivate potential adventitious
viruses, with the final formulation consisting of 10%--18% protein. Both HRIGs are standardized at an average potency value of 150 IU per mL, and supplied in 2-mL (300
IU)
vials for pediatric use and 10-mL (1,500 IU) vials for adult use. The recommended dose is 20 IU/kg (0.133 mL/kg) body
weight. Both HRIG preparations are considered equally efficacious when used as described in these recommendations.

These products are made from the plasma of hyperimmunized human donors that, in theory, might contain infectious
agents. Nevertheless, the risk that such products will transmit an infectious agent has been reduced substantially by screening
plasma donors for previous exposure to certain viruses, by testing for the presence of certain current virus infections, and by
inactivating and/or removing certain viruses. No transmission of adventitious agents has been documented after administration of
HRIGs licensed in the United States.

Three large retrospective cohort studies were identified that describe differences in rabies mortality between
rabies-exposed persons (persons who were exposed to proven or suspected rabid animals) who were vaccinated with older formulations of
rabies vaccine compared with similarly exposed persons who were not administered prophylaxis
(41,44,46). In one 1923 study of 2,174 persons bitten by "presumably rabid" dogs in India, 2.9% of persons vaccinated with 1% Semple nerve tissue
rabies vaccine (NTV) subcutaneously for 14 days died from rabies compared with 6.2% of unvaccinated persons
(41). Another study of persons bitten by assumed infective rabid animals (i.e., one or more other persons bitten by the same animal died from
rabies) during 1946--1951 indicated that 8.3% of persons "completely treated" with 5% Semple rabies vaccine, 23.1% of
"incompletely treated", and 43.2% of unvaccinated persons died from rabies
(46). A third study in Thailand in 1987 documented no
deaths among 723 persons bitten by dogs (661 of these persons were bitten by confirmed rabid dogs) who received one of three
rabies vaccines: Semple vaccine (n = 427), HDCV (n = 257), or duck embryo vaccine (n = 39)
(44). However, 45% (nine of 20) of unvaccinated persons who were bitten by confirmed rabid dogs died from rabies. All of the persons who died were
severely bitten on the face, neck, or arms. All unvaccinated persons who survived after having been bitten by confirmed rabid dogs were
bitten either on the legs or feet. Although these studies describe outcomes of persons receiving older formulations of rabies vaccines
that are not used in the United States, they demonstrate that a majority of persons bitten by known rabid dogs did not acquire
rabies and provide historical evidence of a substantial protective effect of rabies vaccination after rabies exposure.

The effectiveness of cell culture rabies vaccine plus rabies IgG in preventing human deaths after rabies exposure has
been demonstrated in certain studies
(18,19,30--32,39,45). One prospective study described 10 children (aged <12 years) and
32 adults who had been administered HRIG
(Hyperrab®, Cutter Laboratories, Berkeley, CA, USA) and 5 IM doses of
HDCV (L'Institut Merieux, Lyons, France) after exposure to suspected or confirmed rabid animals (brain-tissue positive by
fluorescent antibody testing) (30). All exposed persons
remained rabies-free during 5 years of observation. Another study
investigated outcomes for 90 persons with high-risk exposures (bites or direct exposure to saliva from animals shown to be rabid by
fluorescent antibody tests or bites from wild carnivores or bats that were not available for testing) who were treated with HRIG and
5 IM doses of HDCV (Wyeth Laboratories, Radnor, PA)
(18). All patients, including 21 who were bitten by proven rabid
animals (brain tissue fluorescent antibody positive), were rabies-free after 10--18 months of follow-up. A third study documented
45 persons severely bitten by confirmed rabid animals (brain tissue fluorescent antibody positive) who were administered RIG
of mule origin and 5 IM doses of HDCV (L'Institut Merieux)
(19). No rabies-related deaths were documented 6--12
months after exposure. A fourth study indicated no human rabies cases in 12 months of follow-up among 45 patients receiving
HRIG (Berirab®) and 6 IM doses of PCECV (Behringwerke
Research Laboratories, Marburg, West Germany) after contact
with proven rabid animals (brain tissue fluorescent antibody positive)
(32). Other studies examining outcomes for persons
with varying degrees of exposure to confirmed rabid animals who were administered 6 doses of PCECV IM with or without
HRIG also reported no rabies deaths in 12--15 months
of follow-up (39,45). Several studies also have demonstrated the effectiveness
of intradermal (ID) administration of cell culture rabies vaccine with or without RIG (of human or equine origin) in
preventing rabies among exposed humans
(33--35,37).

Two studies demonstrated the role of RIG administration in conjunction with vaccine in rabies postexposure
prophylaxis (42,43). The first described quantitative serologic outcomes in 29 persons severely bitten by a rabid wolf and demonstrated
the
importance of rabies antiserum administration in the establishment of an early, passive, rabies virus neutralizing antibody
level in patients and protection against rabies
(40,43). Among five patients treated with 2 doses of rabies antiserum and NTV for
21 days, all had detectable levels of rabies virus neutralizing antibody during the first 5 days and all survived. Among seven
patients treated with 1 dose of antiserum in addition to NTV, all had detectable antibody during the first 5 days, but four of six had
low antibody titers by day 21. One of the seven failed to develop more than a very low antibody level beyond day 7 and
eventually died from rabies. Among the five persons treated with NTV without antiserum, none had detectable antibody levels
before day 19, and three died from rabies. In the second study, none of 27 persons severely wounded by rabid animals in China who
were treated with purified hamster kidney cell (PHKC) rabies vaccine plus horse-origin rabies immune
serum died from rabies (42). In contrast, all three severely wounded persons treated with PHKC alone died.

Effectiveness of Rabies Postexposure Prophylaxis: Animal Studies

During the preceding four decades, results of experimental studies using various animal species have supported the use of
cell culture-based vaccines for protection against rabies
after infections. For example, a postexposure prophylaxis
experiment conducted in 1971 in rhesus monkeys using an experimental purified, concentrated tissue-culture vaccine alone, or in combination
with homologous antirabies serum, demonstrated that a single administration of tissue-culture vaccine after exposure to rabies
virus provided substantial (seven of eight animals) protection against the development of rabies. In addition to demonstrating
that homologous or heterologous antirabies serum alone resulted in poor protection from rabies (63%--88% mortality), the
experimental data suggested that highly concentrated, purified tissue-culture vaccine might be effective for postexposure
prophylaxis in humans (47). A study in 1981 documented limited protection against a lethal rabies virus challenge in goats who
received ERA vaccine with or without antirabies goat serum
(48). In cattle, another livestock species, the superiority of tissue culture
vaccine over brain-origin vaccine was demonstrated
(49). Similarly, in sheep, vaccine alone provided limited protection, but vaccine
in combination with polyclonal IgG provided the best outcome
(50). A 1989 evaluation of postexposure prophylaxis
administered to dogs demonstrated similar findings. The combination of serum and vaccine provided nearly complete protection
compared with animals receiving vaccine only and nontreated controls
(51).

Previous animal postexposure research focused primarily on interventions against traditional rabies viruses. However,
new causative agents of rabies continue to emerge, as demonstrated by the recent description of four novel lyssaviruses from bats
in Eurasia, Aravan (ARAV), Khujand (KHUV), Irkut (IRKV), and West Caucasian bat virus (WCBV)
(52,53). The combined effect of RIG and vaccine after exposure to these four new isolates was investigated in a Syrian hamster model, using
commercially available human products or an experimental mAb
(54). Conventional rabies postexposure prophylaxis provided little
or no protection against all four new bat viruses. In general, protection was inversely related to the genetic distance between the
new isolates and traditional rabies viruses, which demonstrated the usefulness of this animal model in estimating the potential
impact of these new lyssaviruses on human and domestic animal health.

Immunogenicity of Rabies Postexposure Prophylaxis

To assess the ability of rabies postexposure prophylaxis to elicit rabies virus neutralizing antibodies in humans, studies
were reviewed that documented antibody responses to rabies postexposure prophylaxis. Four studies of antibody responses to
rabies postexposure prophylaxis with 5 IM doses of HDCV with or without HRIG were identified
(30,55--57). Because no studies were identified that examined antibody responses to postexposure or simulated postexposure prophylaxis with 5 IM doses of
the licensed PCECV vaccine
(RabAvert®) plus HRIG, a study reporting antibody responses to 6 IM doses of another
PCECV formulation (Rabipur®, Novartis Vaccines and Diagnostics) administered with or without HRIG was reviewed
(36). In a randomized trial, all persons receiving HRIG and 5 IM doses of HDCV
(Imovax® Rabies) developed rabies virus antibody
titers >0.5 IU/mL lasting up to 42 days after prophylaxis initiation
(56). In a 1999 case-series, among 40 persons with diverse
histories of exposure to animals suspected of having rabies, all persons who received 5 IM doses of HDCV with or without
HRIG seroconverted or had increases in baseline serum antibody titers after the fifth vaccine dose (geometric mean titer [GMT] =
6.22 IU/mL) (57). Furthermore, a significantly higher mean antibody titer was observed in the group that received HDCV
and HRIG (GMT = 12.3 IU/mL; standard error [SE] = 2.9) than in the group that received HDCV alone (GMT = 8.5 IU/mL;
SE = 1.6; p=0.0043). In a randomized, modified double-blind, multicenter, simulated postexposure trial, 242 healthy adult
volunteers were administered HRIG
(Imogam® Rabies-HT) and 5 IM doses of either HDCV
(Imovax® Rabies) or a
chromatographically purified Vero-cell rabies vaccine (CPRV)
(55). All participants had rabies virus neutralizing antibody titers
>0.5 IU/mL by day 14 and maintained this level through day 42. Participants receiving HDCV had higher GMTs on days 14 and 42 than
did
participants receiving CPRV. In the prospective study comparing rabies neutralizing antibodies in the serum of children
compared with adults following postexposure prophylaxis, all 25 adults and eight children tested on day 14 had rabies virus
neutralizing antibody concentrations >0.5 IU/mL
(30). In addition, no differences in antibody titer were observed between adults
and children, and all persons remained alive during the 5 years of follow-up.

Effectiveness of Rabies Pre-Exposure Prophylaxis: Animal Studies

Because no studies exist on the effectiveness of rabies pre-exposure prophylaxis in preventing rabies deaths in humans,
literature was reviewed on the effectiveness of pre-exposure vaccination in animal models. The effectiveness of rabies vaccine has
been appreciated for most of the 20th century on the basis of animal experiments. Commercial rabies vaccines are licensed for
certain domestic species, all of which entail the direct demonstration of efficacy after the administration of a single pre-exposure
dose, and observed protection from rabies virus challenge for a minimum duration of 1--4 years after vaccination of captive
animals. In addition, rabies pre-exposure vaccine research varies typically either by modification of standard regimens of vaccination
or the relative antigenic value or potency of vaccine administration to animals. For example, at least five studies involved
animals challenged with rabies viruses (challenge standard virus [CVS] or street rabies virus isolates) and other lyssaviruses (European
bat lyssavirus [EBL] 1, EBL2, Australian bat lyssavirus [ABL], and WCBV, IRKV, ARAV, KHUV) after primary vaccination
with PCECV (58) or HDCV (54,58--62). Two of seven studies reported seroconversion in mice and humans. Complete
protection of animals from rabies virus infection was observed in all experiments that used PCECV or HDCV IM for primary
vaccination except in one group that had been challenged by CVS through the intracranial route and experienced 5% mortality
(59). Evaluation of crossprotection of HDCV against WCBV, ARAV, IRKV, KHUV, and ABL through IM challenge showed
44%, 55%, 67%, 89% and 79% survival, respectively
(54). These studies demonstrated the usefulness of commercial human
vaccines when administered to animals, with resulting protection dependent on the relative degree of phylogenetic relatedness
between the rabies vaccine strain and the particular lyssavirus isolate.

Immunogenicity of Rabies Pre-Exposure Prophylaxis: Human Studies

Thirteen studies were identified that provide evidence of the effectiveness of pre-exposure rabies vaccination in eliciting
an adaptive host immune response in humans. The outcomes of interest for these studies
(29,63--74) include the two working definitions of adequate rabies virus neutralizing
antibody reference values that have been developed to define an
appropriate, intact adaptive host response to vaccination: antibody titers of 0.5 IU/mL or complete virus neutralization at a 1:5
serum dilution by RFFIT (26).

Multiple studies comparing different pre-exposure prophylaxis regimens provide evidence that vaccination with 3 IM doses
of cell culture rabies vaccine (the recommended pre-exposure regimen) result in neutralizing antibody titers
>0.5 IU/mL by days 14 (70,71), 21
(63,74), 28 (64,69,72), or 49
(67,68,75) after primary vaccination. One study in 1987 documented
antibody responses in 177 healthy student volunteers aged 18--24 years following primary vaccination with either PCECV
(Behringwerke) or HDCV (Behringwerke) (71). On day 14 after vaccination (first dose administered on day 0), no significant difference
in GMT was observed between participants who received 3 IM doses of PCECV on days 0, 7, and 21 (GMT = 5.9
IU/mL) compared with persons who received 3 IM doses of HDCV (GMT = 4.4
IU/mL). On day 42, the GMT of the HDCV group was significantly higher than that of the PCECV group (13.7 IU/mL versus 8.4 IU/mL; p<0.025). Another study
documented similar antibody responses to primary vaccination with HDCV in healthy veterinary students
(64). The GMT of persons receiving 3 IM doses of HDCV on days 0, 7, and 28 was 10.2 IU/mL (range: 0.7--51.4) on day 28 and 37.7 IU/mL (range:
5.4--278.0) on day 42. Another study documented even higher GMTs among 78 volunteers in a randomized trial studying
differences between primary vaccination with PCECV (Behringwerke) and HDCV (L'Institut Merieux) administered IM or ID
on days 0, 7, and 28 (29). The day 28 GMT among persons receiving HDCV IM (GMT = 239 RFFIT titer/mL; range:
56--800) was significantly higher than the GMT among persons receiving PCECV IM (GMT = 138 RFFIT titer/mL; range:
45--280). On days 50 and 92, no significant difference in GMT was observed between the two groups in which vaccine was
administered IM, and the GMTs of the IM groups were significantly higher than the ID groups. Another study also observed higher
antibody titers on days 49 and 90 and 26 months after primary vaccination with HDCV
(Imovax® Rabies) when the vaccine
was administered IM compared with ID on days 0, 7, and 28
(68). A randomized trial was conducted to determine the
equivalence and interchangeability of PCECV
(RabAvert®) and HDCV
(Imovax® Rabies) administered IM on days 0, 7, and 28 for
rabies pre-exposure prophylaxis to 165 healthy, rabies vaccine naïve veterinary students
(66). No significant difference in GMT was observed among the HDCV and PCECV groups on days 28 and 42.

Although the 3-dose rabies pre-exposure prophylaxis series has been the standard regimen recommended by WHO
(17) and ACIP (26), a 2-dose pre-exposure series has been used previously in some countries
(76). One study compared antibody responses in persons receiving 2 (days 0 and 28) versus 3 (days 0, 7, and 28) IM doses of either HDCV (Pasteur
Merieux Connaught, Lyon, France) or purified Vero cell
rabies vaccine (PVRV) (Pasteur Merieux Connaught) and
indicated that the cohort seroconversion rate decreased more rapidly among persons receiving 2 doses compared with those receiving 3
doses (p<0.001), indicating superior longer term immunogenicity when 3 vaccine doses were administered
(73).

In addition to the rapidity of the immune response resulting from rabies pre-exposure vaccination, another important
consideration is the length of duration or persistence of the immune response. One study reported rapid declines in GMT at 4
months after initial vaccination among persons receiving 3-dose primary vaccination with HDCV (L'Institut Merieux) or PVRV
(L'Institut Merieux) on days 0, 7, and 21 followed by stabilization of the antibody level through 21 months
(63). Another study observed persistent GMTs among persons
receiving 3-dose (days 0, 7, and 28) primary vaccination with PCECV (Behringwerke)
and HDCV (L'Institut Merieux) IM on day 365 (PCECV GMT = 189 RFFIT titer/mL; range: 53--1400; HDCV GMT =
101 RFFIT titer/mL; range: 11--1400) and day 756 (PCECV GMT = 168 RFFIT titer/mL; range: 50--3600; HDCV GMT =
92 RFFIT titer/mL; range: 11--480) after initial vaccination
(29). On day 387 post vaccination, another study indicated that
the GMT among persons receiving PCECV
(RabAvert®) IM on days 0, 7, and 28 (GMT = 2.9 IU/mL) was significantly
higher than the GMT in the HDCV
(Imovax® Rabies) group (GMT = 1.5 IU/mL; p<0.05)
(66). All persons vaccinated with PCECV had antibody titers >0.5 IU/mL on days 387, as did 95.7% of persons vaccinated with HDCV. Another study indicated that
all persons receiving PCECV (Behringwerke) IM on days 0, 7, and 21 maintained antibody titers >0.5 IU/mL 2 years after
primary vaccination (71). In summary, rabies virus neutralizing antibody titers >0.5 IU/mL were observed in all persons at 180 days
and 96.8% at 365 days after initial vaccination
(72), 94% of persons at 21 months after initial vaccination
(63), and all persons tested at 26 months after primary vaccination
(77).

An important use of rabies pre-exposure prophylaxis is to prime the immune response to enable a rapid anamnestic
response to postexposure booster vaccination and simplify the postexposure prophylaxis requirements for previously vaccinated
persons. One study observed antibody responses to 1- or 2-dose (days 0 and 3) IM booster vaccinations with PCECV
(RabAvert®) in persons who had received primary vaccination with either PCECV IM or HDCV IM 1 year earlier
(66). All participants who had initially received PCECV primary vaccination and 66 of 69 (96%) who had initially
received HDCV primary vaccination had titers >0.5 IU/mL before booster vaccination. No significant differences in GMT were observed between 1- and
2-dose booster groups on days 3 (2-dose GMT = 2.07 IU/mL; 1-dose GMT = 2.87 IU/mL), seven (2-dose GMT = 51.67 IU/mL;
1-dose GMT = 51.23 IU/mL) and 365 (2-dose GMT = 30.60 IU/mL;
1-dose GMT = 26.10 IU/mL) (66). However, a
significantly higher GMT was observed on day 21 for persons receiving
2-dose boosters (GMT = 151.63 IU/mL) compared with
1-dose boosters (GMT = 120.91 IU/mL). All persons tested at day 365 post-booster dose in both 1- and 2-dose booster
groups had rabies virus neutralizing antibody titers
>0.5 IU/mL regardless of whether PCECV or HDCV was used for primary
vaccination. Another study documented rapid antibody responses to a single booster dose of HDCV
(Imovax® Rabies) or CPRV (Pasteur Merieux Connaught), with all persons in both groups exhibiting antibody titers
>0.5 IU/mL on days 7 and 14 post-booster dose
(72).

Safety of Rabies Biologics

Eight studies regarding the safety of rabies biologics used in postexposure or simulated postexposure settings
(36,55--57,78--81) and eight studies of safety in pre-exposure settings were identified
(63--65,68,71,72,82). Three identified studies
investigated reports of adverse events in both postexposure and pre-exposure settings
(14,83,84). Reviews of relevant
bibliographies identified one additional study examining the safety of PCECV when used without HRIG for postexposure prophylaxis
in children (85).

HDCV

Studies of the use of HDCV reported local reactions (e.g., pain at the injection site, redness, swelling, and induration)
among 60.0%--89.5% of recipients
(63--65,68,72). Local reactions were more common than systemic reactions. Most local
reactions were mild and resolved spontaneously within a few days. Local pain at the injection site was the most frequently
reported adverse reaction occurring in 21%--77% of vaccinees
(24,63,68,71,72,80). Mild systemic reactions (e.g., fever, headache, dizziness,
and gastrointestinal symptoms) were reported in 6.8%--55.6% of recipients
(63,64,68,72).

Systemic hypersensitivity reactions have been reported in up to 6% of persons receiving booster vaccination with
HDCV following primary rabies prophylaxis, 3% occurring within 1 day of receiving boosters, and 3% occurring 6--14 days
after boosters (82). In one study, hypersensitivity reactions (e.g., urticaria, pruritic rash, and angioedema) were
reported in 5.6% (11 of 99) of schoolchildren aged 5--13 years following pre-exposure prophylaxis with IM HDCV
(72). Angioedema was observed in 1.2% of these school children after booster doses of HDCV 1 year after primary vaccination with HDCV. In 46 months
of surveillance for adverse events following HDCV administration during 1980--1984, CDC received reports of 108
systemic allergic reactions (ranging from hives to anaphylaxis) following HDCV (11 per 10,000 vaccinees)
(14). These included nine cases of presumed Type I immediate hypersensitivity (one of 10,000), 87 cases of presumed Type III hypersensitivity (nine
of 10,000), and 12 cases of hypersensitivity of indeterminate type. All nine of the presumed immediate hypersensitivity
reactions occurred during either primary pre-exposure or postexposure vaccination. Most (93%) of the Type III hypersensitivity
reactions were observed following booster vaccination. Systemic allergic reactions have been associated with the presence
of betapropiolactone-altered human albumin in HDCV and the development of immunoglobulin E (IgE) antibodies to this
allergen (82,86). No deaths resulting from these reactions were reported.

In four studies investigating the safety of rabies postexposure prophylaxis with both HRIG and HDCV, no serious
adverse events were observed (55--57,78). Local reactions were common, and pain at the injection site was reported by 7%--92%
of participants (55--57). Studies of the frequency of systemic adverse reactions following rabies vaccination are limited by
small sample sizes. Systemic adverse reactions were not
observed in any of the participants in one study with a relatively small
sample size (78). In two other studies in which adverse events were collected using patient self-monitoring forms and
investigator interviews at each visit, systemic reactions were reported by 76%--100% of participants
(55,56). However, none of these reported systemic adverse events was considered to be serious.

Rare, individual case reports of neurologic adverse events following rabies vaccination have been reported, but in none of
the cases has causality been established. Four cases of neurologic illness resembling Guillain-Barré syndrome occurring after
treatment with HDCV were identified
(13,87--89). One case of acute neurologic syndrome involving seizure activity was
reported following the administration of HDCV and HRIG
(90). Other central and peripheral nervous system disorders have been
temporally associated with HDCV vaccine
(91).

PCECV

In studies of PCECV use, local reactions (e.g., pain at the injection site, redness, swelling, and induration) were
reported among 11%--57% of recipients
(29,79,84). Local pain at the injection site, the most common local reaction, was reported
in 2%--23% of vaccinees (29,71,79,81,83,85). Systemic
reactions were less common and have been reported in 0--31% of
vaccine recipients (79,83,84). One study investigated adverse events among 271 children in India who received
rabies postexposure prophylaxis with PCECV IM without HRIG following bites from suspected or confirmed rabid dogs
(85). Overall, 7% of the children experienced mild to moderate clinical reactions. The most frequently reported reaction was local pain after the first
or second dose (4%). Another study documented clinical reactions in 29 persons administered 6 IM doses of PCECV with (n
= four) or without HRIG following bites by suspected rabid stray dogs. No serious
adverse events were observed during the course of or after prophylaxis
(36). Another case report documented one case of neurologic illness resembling Guillain-Barré
syndrome after vaccination with PCECV in India
(92).

A retrospective review of adverse events following administration of PCECV was conducted using data from the United
States Vaccine Adverse Events Reporting System (VAERS)
(93). During 1997--2005, approximately 1.1 million doses of PCECV
were distributed in the United States and 336 reports describing
adverse events following PCECV administration were received
by VAERS (30 events per 100,000 doses distributed and three serious events per 100,000 doses distributed). A total of 199
reported adverse events (4% serious [i.e., adverse events that involve hospitalization,
life-threatening illness, disability, or death])
occurred following administration of PCECV alone, and 137 (12% serious)
occurred following PCECV administered
concomitantly with another vaccine or following postexposure prophylaxis (PCECV co-administered with HRIG). Among the 312
nonserious adverse events, the most frequently reported were headache, fever, myalgia, nausea, and weakness. A limitation of VAERS is
that causality between vaccine administration and reported adverse events cannot be established
(94). No deaths or rabies cases were reported following administration of PCECV.

HRIG

In a clinical trial involving 16 volunteers in each group, participants receiving HRIG plus placebo (administered to
mimic vaccine) commonly reported local reactions (100% in conventionally produced HRIG group, 75% in heat-treated HRIG
group), including pain/tenderness (100% conventional HRIG, 50% heat-treated HRIG), erythema (63% conventional, 25%
heat-treated), and induration (50% conventional, 31% heat-treated)
(56). Systemic reactions were reported in 75% of participants
in the conventional HRIG group and 81% in the heat-treated group. Headache was the most commonly reported systemic
reaction (50% conventional, 69% heat-treated). The majority of the reported local and systemic reactions were mild, and no
significant differences were observed in the frequency of adverse events between treatment groups. No serious adverse events,
including immediate hypersensitivity reactions or immune-complex-like disease, were reported.

Cost-Effectiveness of Rabies Postexposure Prophylaxis

ACIP's charter requires the committee, when deliberating recommendations for vaccine use in the United States, to
consider the cost and benefits of potential recommendations. Cost-effectiveness studies combine different types of data (e.g.,
epidemiologic, clinical, cost, and vaccine effectiveness), and the results from such studies allow public health officials, medical
practitioners, and the public to make more informed decisions when evaluating the risk for disease against the cost of the
vaccine, including vaccine-related side effects.

CDC analyzed the cost-effectiveness of rabies postexposure prophylaxis for each of eight contact (risk of transmission)
scenarios, with the outcome being the net cost (in dollars) per life saved (in 2004 dollars). The perspective was societal,
which means that all costs and all benefits were included,
regardless of who pays and who benefits. For each
risk-of-transmission scenario, three cost-effectiveness ratios were calculated: average, most, and least cost-effective. Average cost-effective ratios
were calculated using median transmission risk values (Table 2) and average cost of postexposure prophylaxis. Most
cost-effective ratios were calculated using greatest (largest) transmission risk values and least cost of postexposure prophylaxis. Least
cost-effective ratios were calculated using lowest transmission risk and greatest cost of postexposure prophylaxis. The analysis
assumed that the direct medical costs associated with postexposure prophylaxis included 1 dose of HRIG ($326--$1,434), 5
doses of HDCV ($113--$679 each), hospital charges ($289--$624), and physician charges ($295--$641)
(95). Indirect costs included travel, lost wages, alternative medicine, and other costs ($161--$2,161)
(96). A societal perspective requires the valuation of
the loss of productivity to society caused by premature death. Therefore, human life lost was valued using the average present
value, in 2004 dollars, of expected future lifetime earnings and housekeeping services ($1,109,920)
(97). All costs were adjusted to 2004 dollars using the medical care price index. The study also assumed that rabies postexposure prophylaxis, when
administered according to these recommendations, was essentially 100% effective in preventing a clinical case of
human rabies. The probabilities of rabies transmission to a human following possible contact with different species of potentially rabid animals
was assessed by a panel of experts using the Delphi methodology, except for "animal tests positive for rabies" when probabilities
were obtained from a previous study (98) (Table 2).

Under all three cost-effectiveness scenarios, the analysis determined that it is always cost saving to administer
postexposure prophylaxis if a patient is bitten by a rabid animal that has tested positive for rabies or if a patient is bitten by a reservoir or
vector species (e.g. skunk, raccoon, bat, or fox bite in the United States or dog bite in countries with dog variant rabies), even if
the animal is not available for testing. For all other transmission risk situations, the average net cost effectiveness ratio was always
a net cost per life saved (range: $2.9 million per life saved following a bite from an untested cat to $4 billion per life
saved following a lick from an untested dog). The wide range of probabilities of risk for transmission for the bat bite scenario
resulted in the widest range of cost-effectiveness ratios (Table 2). Until more precise estimates of risk for transmission are obtained,
these estimates illustrate the difficulty clinicians and public health officials will continue to encounter in unequivocally
determining the cost-effectiveness of providing PEP.

Rabies Postexposure Prophylaxis

Rationale for Prophylaxis

ACIP (26) and WHO (25) recommend that prophylaxis for the prevention of rabies in humans exposed to rabies virus
should include prompt and thorough wound cleansing followed by passive vaccination with HRIG and vaccination with cell
culture
rabies vaccines. Administration of rabies postexposure prophylaxis is a medical urgency, not a medical emergency. Because
rabies biologics are valuable resources that are periodically in short supply, a risk assessment weighing potential adverse
consequences associated with administering postexposure prophylaxis along with their severity and likelihood versus the actual risk for
the person acquiring rabies should be conducted in each situation involving a possible rabies exposure. Because the balance
of benefit and harm will differ among exposed persons on the basis of the risk for infection, recommendations regarding
rabies postexposure prophylaxis are dependent upon associated risks including 1) type of exposure, 2) epidemiology of animal rabies
in the area where the contact occurred and species of animal involved, and 3) circumstances of the exposure incident. The
reliability of this information should be assessed for each incident. The decision of whether to initiate rabies postexposure prophylaxis
also depends on the availability of the exposing animal for observation or rabies testing (Table 3). Because the epidemiology
and pathogenesis of rabies are complex, these recommendations cannot be specific for every possible circumstance. Clinicians
should seek assistance from local or state public health officials for evaluating exposures or determining the need for
postexposure management in situations that are not routine. State and local officials have access to CDC rabies experts for particularly
rare situations or difficult decisions.

Types of Exposure

When an exposure has occurred, the likelihood of rabies infection varies with the nature and extent of that exposure.
Under most circumstances, two categories of exposure (bite and nonbite) should be considered. The most dangerous and
common route of rabies exposure is from the bite of a rabid mammal. An exposure to rabies also might occur when the virus, from
saliva or other potentially infectious material (e.g., neural tissue), is introduced into fresh, open cuts in skin or onto mucous
membranes (nonbite exposure). Indirect contact and activities (e.g., petting or handling an animal, contact with blood, urine or
feces, and contact of saliva with intact skin) do not constitute exposures; therefore, postexposure prophylaxis should not be
administered in these situations. Exposures to bats deserve special assessment
because bats can pose a greater risk for infecting
humans under certain circumstances that might be considered inconsequential from a human perspective (i.e., a minor bite or
lesion). Human-to-human transmission occurs almost exclusively as a result of organ or tissue transplantation. Clinicians should
contact local or state public health officials for assistance in determining the likelihood of a rabies exposure in a specific situation.

Bite exposures.Any penetration of the skin by teeth constitutes a bite exposure. All bites, regardless of body site or
evidence of gross trauma, represent a potential risk. The risk for transmission varies in part with the species of biting animal, the
anatomic site of the bite, and the severity of the wound
(98). Although risk for transmission might increase with wound severity,
rabies transmission also occurs from bites by some animals (e.g., bats) that inflict rather minor injury compared with
larger-bodied carnivores, resulting in lesions that are difficult to detect under certain circumstances
(8,99--103).

Nonbite exposures. Nonbite exposures from animals very rarely cause rabies. However, occasional reports of nonbite
transmission suggest that such exposures require assessment to determine if sufficient reasons exist to consider postexposure
prophylaxis (104). The nonbite exposures of highest risk
appear to be among surgical recipients of corneas, solid
organs, and vascular tissue transplanted from patients who died of rabies and persons exposed to large amounts of aerosolized rabies virus. Two
cases of rabies have been attributed to probable aerosol exposures in laboratories, and two cases of rabies have been attributed
to possible airborne exposures in caves containing millions of free-tailed bats
(Tadarida brasiliensis) in the Southwest.
However, alternative infection routes can not be discounted
(105--109). Similar airborne incidents have not occurred in approximately
25 years, probably because of elevated awareness of such risks resulting in increased use of appropriate preventive measures.

The contamination of open wounds or abrasions (including scratches) or mucous membranes with saliva or
other potentially infectious material (e.g., neural tissue) from a
rabid animal also constitutes a nonbite exposure. Rabies
virus is inactivated by desiccation, ultraviolet irradiation, and other factors and does not persist in the environment. In general, if
the suspect material is dry, the virus can be considered noninfectious. Nonbite exposures other than organ or tissue transplants
have almost never been proven to cause rabies, and postexposure prophylaxis is not indicated unless the nonbite exposure met
the definition of saliva or other potentially infectious
material being introduced into fresh, open cuts in skin or onto
mucous membranes.

Bat Exposures. The most common rabies virus variants responsible for human rabies in the United States are
bat-related; therefore, any potential exposure to a bat requires a thorough evaluation. If possible, bats involved in potential human
exposures should be safely collected and submitted for
rabies diagnosis. Most submitted bats (approximately 94%)
(110) will not be rabid and such timely diagnostic assessments rule out the need for large investments in risk assessments and unnecessary prophylaxis.

The risk for rabies resulting from an encounter with a bat might be difficult to determine because of the limited
injury inflicted by a bat bite (compared with more obvious wounds caused by the bite of terrestrial carnivores), an inaccurate
recall of a bat encounter that might have occurred several weeks or months earlier, and evidence that some bat-related rabies viruses
might be more likely to result in infection after inoculation into superficial epidermal layers
(111). For these reasons, any direct
contact between a human and a bat should be evaluated for an exposure. If the person can be reasonably certain a bite, scratch, or
mucous membrane exposure did not occur, or if the bat is available for testing and is negative for presence of rabies virus,
postexposure prophylaxis is not necessary. Other situations that might qualify as exposures include finding a bat in the same room as a
person who might be unaware that a bite or direct contact had occurred (e.g., a deeply sleeping person awakens to find a bat in the
room or an adult witnesses a bat in the room with a previously unattended child, mentally disabled person, or intoxicated
person). These situations should not be considered exposures if rabies is ruled out by diagnostic testing of the bat, or
circumstances suggest it is unlikely that an exposure took place. Other household members who did not have direct contact with the bat or
were awake and aware when in the same room as the bat should not be considered as having been exposed to
rabies. Circumstances that make it less likely that an undetected
exposure occurred include the observation of bats roosting or flying in a room open
to the outdoors, the observation of bats outdoors or in a setting where bats might normally be present, or situations in which
the use of protective covers (e.g., mosquito netting) would reasonably be expected to preclude unnoticed contact. Because of
the complexity of some of these situations, consultation with state and local health departments should always be sought. If
necessary, further guidance can be sought from CDC and experts in bat ecology.

During 1990--2007, a total of 34 naturally acquired bat-associated human cases of rabies was reported in the United States.
In six cases, a bite was reported; in two cases, contact with a bat and a probable bite were reported; in 15 cases, physical contact
was reported (e.g., the removal of a bat from the home or workplace or the presence of a bat in the room where the person had
been sleeping), but no bite was documented; and in 11 cases, no bat encounter was reported. In these cases, an unreported
or undetected bat bite remains the most plausible hypothesis because the genetic sequences of the human rabies viruses
closely matched those of specific species of bats. Clustering of human cases associated with bat exposures has never been reported in
the United States (e.g., within the same household or among a group of campers where bats were observed during their
activities) (8,101,110).

Human-to-Human Exposures.Human-to-human transmission can occur in the same way as animal-to-human
transmission (i.e., the virus is introduced into fresh open cuts in skin or onto mucous membranes from saliva or other potentially
infectious material such as neural tissue). Organ and tissue transplantation resulting in rabies transmission has occurred among 16
transplant recipients from corneas (n = eight), solid organs (n = seven), and vascular tissue
(n = one). Each of the donors died of an illness compatible with or proven to be rabies
(10,112--123). The 16 cases occurred in five countries: the United States
(five cases: one corneal transplant transmission, three solid organ transmissions, and one vascular graft transmission), Germany
(four cases), Thailand (two cases), India (two cases), Iran (two cases), and France (one case).

No documented laboratory-diagnosed cases of human-to-human rabies transmission have been documented from a bite
or nonbite exposure other than the transplant cases
(124). At least two cases of human-to-human rabies transmission in
Ethiopia have been suggested, but rabies as the cause of death was not confirmed by laboratory testing
(125). The reported route of exposure in both cases was direct salivary contact from another human (i.e., a bite and a kiss). Routine delivery of health care
to a patient with rabies is not an indication for postexposure prophylaxis unless the health-care worker is reasonably certain that
he or she was bitten by the patient or that his or her mucous membranes or nonintact skin was exposed directly to
potentially infectious saliva or neural tissue. Adherence
to standard precautions for all hospitalized patients as outlined by the
Hospital Infection Control Practices Advisory Committee will minimize the need for postexposure prophylaxis in such situations
(126). Staff should wear gowns, goggles, masks, and gloves, particularly during intubation and suctioning
(25).

Animal Rabies Epidemiology

Bats.Rabid bats have been documented in the 49 continental states, and bats are increasingly implicated as important
wildlife reservoirs for variants of rabies virus transmitted to humans
(5,101,102,110). Transmission of rabies virus can occur
from minor, seemingly underappreciated or unrecognized bites from bats
(8,99--103). Laboratory data support a hypothesis that
bat rabies virus variants associated with silver-haired bats
(Lasionycteris noctivagans) and eastern pipistrelles
(Pipistrellus subflavus) have biologic characteristics that might allow a higher likelihood of infection after superficial inoculation, such as into cells
of epidermal origin (127). Human and domestic animal contact with bats should be minimized, and bats should never be
handled by untrained and unvaccinated persons or be kept as pets
(128).

Wild Terrestrial Carnivores.Raccoons, skunks, and foxes are the terrestrial carnivores most often infected with rabies in
the United States (5). Suggestive clinical signs of rabies among wildlife cannot be interpreted reliably. All bites by such
wildlife should be considered possible exposures to rabies
virus. Postexposure prophylaxis should be initiated as soon as possible
following exposure to such wildlife, unless the animal is available for diagnosis and public health authorities are facilitating
expeditious laboratory testing, or if the brain tissue from the animal has already tested negative. Wild terrestrial carnivores that are
available for diagnostic testing should be euthanized as soon as possible (without unnecessary damage to the head), and the brain
should be submitted for rabies diagnosis
(129,130). If the results of testing are negative by immunofluorescence, human rabies
postexposure prophylaxis is not necessary. Other factors that might influence the
urgency of decision-making regarding the initiation
of postexposure prophylaxis before diagnostic results are known include the species of the animal, the general appearance
and behavior of the animal, whether the encounter was provoked by the presence of a human, and the severity and location of bites.

Other Wild Animals. Rodents are not reservoirs of rabies virus. Small rodents (e.g., squirrels, chipmunks, rats, mice,
hamsters, guinea pigs, and gerbils) and lagomorphs (including rabbits and hares) are rarely infected with rabies and have not
been known to transmit rabies to humans
(131,132). During 1990--1996, in areas of the country where raccoon rabies was
enzootic, woodchucks accounted for 93% of the 371 cases of rabies among rodents reported to CDC
(5,133,134). In all cases involving rodents, the state or local health department should be consulted before a decision is made to initiate postexposure
prophylaxis (135).

The offspring of wild animals crossbred to domestic dogs and cats (wild animal hybrids) are considered wild animals by
the National Association of State and Public Health Veterinarians and CSTE. Because the period of rabies virus shedding in
wild animal hybrids is unknown, when such animals bite humans euthanasia and rabies testing of the hybrid animal is the
safest course of action. Vaccination should be discontinued if diagnostic tests of the involved animal are negative for rabies
infection. However, because wolves and dogs have very similar genetic makeup and many animals that are
advertised as "wolf-dogs" might actually be dogs, each wolf hybrid bite situation should be evaluated individually, taking into account the likelihood that it is
a hybrid, the severity of the wound, and the assessment by the bite victim and his or her health-care provider. State or local
health departments should be consulted before a decision is made to euthanize and test an animal. Wild animals and wild
animal hybrids should not be kept as pets
(128)or be publicly accessible. Humans who work with wild animals maintained in
United States Department of Agriculture-licensed research facilities or accredited zoological parks should be educated on
preventing bites and should receive rabies pre-exposure vaccinations. Rabies exposures of these animal handlers might require
booster postexposure vaccinations in lieu of euthanasia and testing of the animal depending on employment requirements.

Domestic Dogs, Cats, and Ferrets. The likelihood of
rabies in a domestic animal varies regionally, and the need for postexposure prophylaxis also varies on the basis of regional epidemiology. The number of reported cases of rabies in
domestic dogs has decreased substantially in the United States, primarily because of improved canine vaccination and stray animal control
programs (5). In the continental United States, rabies among dogs has been reported sporadically along the United
States-Mexico border and in areas of the United States with enzootic wildlife rabies
(5). During 2000--2006, more cats than dogs were
reported rabid in the United States (6). The majority of these cases were associated with the epizootic of rabies among raccoons in
the eastern United States. The large number of rabid cats compared with other domestic animals might be attributed to a
lower vaccination rate among cats because of less stringent cat vaccination laws; fewer confinement or leash laws; and the
nocturnal activity patterns of cats placing them at greater risk for exposure to infected raccoons, skunks, foxes, and bats. In certain
developing countries, dogs remain the major reservoir and vector of rabies and represent an increased risk for rabies exposure in
such countries (136).

A healthy domestic dog, cat, or ferret that bites a person should be confined and observed for 10 days
(128,137,138). Those that remain alive and healthy 10 days after a bite would not have been shedding rabies virus in their saliva and would not
have been infectious at the time of the bite
(25). All domestic dogs, cats, and ferrets kept as pets should be vaccinated against
rabies. Even if they are not, such animals might still be confined and observed for 10 days after a bite to reliably determine the risk
for rabies exposure for the person who was bitten. Any illness in the animal during the confinement period before release should
be evaluated by a veterinarian and reported immediately to the local public health department. If signs suggestive of rabies
develop, postexposure prophylaxis of the bite victim should be initiated. The animal should be euthanized and its head removed
and shipped, under refrigeration, for examination by a qualified laboratory. If the biting animal is stray or unwanted, it should
either be confined and observed for 10 days or euthanized immediately and submitted for rabies diagnosis
(128).

Other Domestic Animals. In all instances of exposure to other domestic animal species, local or state health
department should be consulted before a decision is made to euthanize and test the animal or initiate postexposure prophylaxis
(128).

Circumstances of Biting Incident and Vaccination Status of Exposing Animal

An unprovoked attack by an animal might be more likely than a provoked attack to indicate that the animal is rabid.
Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as provoked.
Other factors to consider when evaluating a potential
rabies exposure include the epidemiology of rabies in the area, the biting
animal's history and health status (e.g., abnormal behavior and signs of illness), and the potential for the animal to be exposed to
rabies (e.g., presence of an unexplained wound or history of exposure to a rabid animal). A dog, cat, or ferret with a history
of continuously current vaccination (i.e., no substantial gaps in vaccination coverage) is unlikely to become infected with
rabies (128,137,139--141). Even after an initial rabies vaccination, young or naïve animals remain at risk for rabies because of
the potential exposures preceding vaccination or before adequate induction of immunity during the 28 days after primary
vaccination (128).

Treatment of Wounds and Vaccination

The essential components of rabies postexposure prophylaxis are wound treatment and, for previously unvaccinated
persons, the administration of both HRIG and vaccine (Table 4)
(142). Administration of rabies postexposure prophylaxis is a
medical urgency, not a medical emergency, but decisions must not be delayed. Incubation periods of more than 1 year have been
reported in humans (143). Therefore, when a documented or likely exposure has occurred, postexposure prophylaxis should be
administered regardless of the length of the delay, provided that compatible clinical signs of rabies are not present in the exposed
person. The administration of postexposure prophylaxis to a clinically
rabid human patient has demonstrated consistent
ineffectiveness (25).

In 1977, WHO recommended a regimen of RIG and 6 doses of HDCV over a 90-day period. This recommendation
was based on studies in Germany and Iran
(19,21). When used in this manner, the vaccine was safe and effective in persons bitten
by animals proven to be rabid and induced an adequate antibody response in all recipients
(19). Studies conducted in the
United States by CDC have documented that a regimen of 1 dose of HRIG and 5 doses of HDCV over a
28-day period was safe and induced an adequate antibody response in all recipients
(18). Clinical trials with PCECV have demonstrated
immunogenicity equivalent to that of HDCV
(144).

Cell culture vaccines have been used effectively with HRIG or RIG of equine origin (ERIG) worldwide to prevent rabies
in persons bitten by various rabid animals
(18,19). Worldwide, WHO estimates that postexposure prophylaxis is initiated on
10--12 million persons annually (144). An estimated 16,000--39,000 persons in the United States receive a full postexposure
course each year (11). Although postexposure prophylaxis has not always been properly administered in the United States, no
failures have been documented since current biologics have been licensed.

Treatment of Wounds

Regardless of the risk for rabies, the optimal medical treatment of animal bite wounds includes the recognition and
treatment of serious injury (e.g., nerve or tendon laceration), avoidance or management of infection (both local and systemic), and
approaches that will yield the best possible cosmetic results
(145). For many types of bite wounds, immediate gentle irrigation
with water or a dilute water povidone-iodine solution markedly decrease the risk for bacterial infection
(146). Care should be taken not to damage skin or tissues. Wound cleansing is especially important in rabies prevention because thorough wound
cleansing alone without other postexposure prophylaxis markedly reduce the likelihood of rabies in animal studies
(147,148). Consideration should be given to the need for a booster dose of tetanus vaccine
(149,150). Decisions regarding the use of
antibiotic prophylaxis (151) and primary wound closure
(152)should be individualized on the basis of the exposing animal species,
size and location of the wound(s), and time interval since the bite. Suturing should be avoided, when possible.

Vaccination

Postexposure antirabies vaccination should always include administration of both passive antibody and vaccine, with
the exception of persons who have ever previously received complete vaccination regimens (pre-exposure or postexposure) with a
cell culture vaccine or persons who have been vaccinated with other types of vaccines and have previously had a documented
rabies
virus neutralizing antibody titer. These persons should receive only vaccine (i.e., postexposure for a person previously
vaccinated). The combination of HRIG and vaccine is recommended for both bite and nonbite exposures reported by persons
who have never been previously vaccinated for rabies, regardless of the interval between exposure and initiation of prophylaxis.
If postexposure prophylaxis has been initiated and appropriate laboratory diagnostic testing (i.e., the direct fluorescent
antibody test) indicates that the exposing animal was not rabid, postexposure prophylaxis can be discontinued.

Rabies IgG Use. HRIG is administered only once (i.e., at the beginning of antirabies prophylaxis) to previously
unvaccinated persons to provide immediate, passive, rabies virus-neutralizing antibody coverage until the patient responds to HDCV
or PCECV by actively producing antibodies. If HRIG was not administered when vaccination was begun (i.e., day 0), it can
be administered up to and including day 7 of the postexposure prophylaxis series
(153). Beyond the seventh day, HRIG is not indicated because an antibody response to cell culture vaccine is presumed to have occurred. Because HRIG can
partially suppress active production of antibody, the dose administered should not exceed the recommended dose
(154). The recommended dose of HRIG is 20 IU/kg (0.133 mL/kg) body weight. This formula is applicable to all age groups, including
children. If anatomically feasible, the full dose of HRIG should be thoroughly infiltrated in the area around and into the wounds.
Any remaining volume should be injected IM at a site distant from vaccine administration. This recommendation for HRIG
administration is based on reports of rare failures of postexposure prophylaxis when less than the full amount of HRIG was
infiltrated at the exposure sites (155). HRIG should never be administered in the same syringe or in the same anatomical site as the
first vaccine dose. However, subsequent doses of vaccine in the
5-dose series can be administered in the same anatomic location
where the HRIG dose was administered, if this is the preferable site for vaccine administration (i.e., deltoid for adults or
anterolateral thigh for infants and small children).

Vaccine Use. Two rabies vaccines are available for use in the United States (Table 1); either can be administered in
conjunction with HRIG at the beginning of postexposure prophylaxis. A regimen of 5 one-mL doses of HDCV or PCECV should
be administered IM to previously unvaccinated persons. The first dose of the 5-dose course should be administered as soon
as possible after exposure. This date is then considered day 0 of the postexposure prophylaxis series.
Additional doses should then be administered on days 3, 7, 14, and 28 after the first vaccination. For adults, the vaccination should always be administered
IM in the deltoid area. For children, the anterolateral aspect of the thigh is also acceptable. The gluteal area should never be used
for HDCV or PCECV injections because administration of HDCV in this area results in lower neutralizing antibody titers
(156).

Deviations from Recommended Postexposure Vaccination Schedules

Every attempt should be made to adhere to the recommended vaccination schedules. Once vaccination is initiated, delays of
a few days for individual doses are unimportant, but the effect of longer lapses of weeks or more is unknown
(157). Most interruptions in the vaccine schedule do not require reinitiation of the entire series
(158). For most minor deviations from the
schedule, vaccination can be resumed as though the patient were on schedule. For example, if a patient misses the dose scheduled for
day 7 and presents for vaccination on day 10, the day 7 dose should be administered that day and the schedule resumed,
maintaining the same interval between doses. In this scenario, the remaining doses would be administered on days 17 and 31. When
substantial deviations from the schedule occur, immune status should be assessed by performing serologic testing 7--14 days
after administration of the final dose in the series.

Postexposure Prophylaxis Outside the United States

Persons exposed to rabies outside the United States in countries where rabies is enzootic might receive postexposure
prophylaxis with regimens or biologics that are not used in the United States, including purified vero cell rabies vaccine
(Verorab, Imovax -- Rabies
vero, TRC
Verorab), purified duck embryo vaccine (Lyssavac
N), and different formulations of
PCECV (Rabipur®) or HDCV
(Rabivac). This information is provided to familiarize physicians with some of the regimens used
more widely abroad. These regimens have not been submitted for approval by the U.S. Food and Drug Administration (FDA) for
use in the United States (37,74,159--168). If postexposure prophylaxis is initiated outside the United States using one of
these regimens or vaccines of nerve tissue origin, additional prophylaxis might be necessary when the patient presents for care in
the United States. State or local health departments should be contacted for specific advice in such cases. Rabies virus
neutralizing antibody titers from specimens collected 1--2 weeks after pre-exposure or postexposure prophylaxis would be considered
adequate if complete neutralization of challenge virus at a 1:5 serum dilution by RFFIT occurs.

Purified ERIG or fractions of ERIG have been used in
developing countries where HRIG might not have been available.
The incidence of adverse reactions after ERIG administration has been low (0.8%--6.0%), and most of those that occurred
were minor (169--171). In addition, unpurified
antirabies serum of equine origin might still be used in some countries where
neither HRIG nor ERIG are available. The use of this antirabies serum is associated with higher rates of serious adverse
reactions, including anaphylaxis (172).

Although no postexposure prophylaxis failures have
occurred in the United States since cell culture vaccines and HRIG
have been routinely used, failures have occurred abroad when less than potent biologics were used, if some deviation was made
from the recommended postexposure prophylaxis protocol, or when less than the recommended amount of RIG was
administered (155,173--175). Specifically, patients who contracted rabies after postexposure prophylaxis might not have had adequate
local wound cleansing, might not have received rabies vaccine injections in the deltoid area (i.e., vaccine was administered in
the gluteal area), or might not have received appropriate infiltration of RIG around the wound site. Substantial delays
between exposure and initiation of prophylaxis are of concern, especially with severe wounds to the face and head, which might
provide access to the central nervous system through rapid viral neurotropism.

Rabies Pre-Exposure Prophylaxis

Pre-exposure rabies prophylaxis is administered for several reasons. First, although pre-exposure vaccination does not
eliminate the need for additional medical evaluation after a rabies exposure, it simplifies management by eliminating the need for
RIG and decreasing the number of doses of vaccine needed. This is particularly important for persons at high risk for being
exposed to rabies in areas where modern immunizing products might not be available or where cruder, less safe biologics might be
used, placing the exposed person at increased risk for adverse events. Second, pre-exposure prophylaxis might offer partial
immunity to persons whose postexposure prophylaxis is delayed. Finally, pre-exposure prophylaxis might provide some protection
to persons at risk for unrecognized exposures to rabies.

Pre-exposure vaccination should be offered to persons in high-risk groups, such as veterinarians and their staff, animal
handlers, rabies researchers, and certain laboratory workers. Pre-exposure vaccination also should be considered for persons
whose activities bring them into frequent contact with rabies virus or potentially rabid bats, raccoons, skunks, cats, dogs, or
other species at risk for having rabies. In addition, some international travelers might be candidates for
pre-exposure vaccination if they are likely to come in contact with animals in areas where dog or other animal rabies is enzootic and immediate access
to appropriate medical care, including rabies vaccine and immune globulin, might be limited. Routine pre-exposure
prophylaxis for the general U.S. population or routine travelers to areas where rabies is not enzootic is not recommended
(176,177).

Primary Vaccination

Three 1.0-mL injections of HDCV or PCECV should be administered IM (deltoid area), one injection per day on days 0,
7, and 21 or 28 (Table 5). The immunogenicity of IM primary vaccination with PCECV and HDCV has been
reviewed. Vaccine preparations for ID administration are no longer available in the United States.

Pre-Exposure Booster Doses of Vaccine

Persons who work with rabies virus in research laboratories or vaccine production facilities (continuous risk category
[Table 6]) (178) are at the highest risk for inapparent exposures. Such persons should have a serum sample tested for rabies
virus neutralizing antibody every 6 months. An IM booster dose (Table 5) of vaccine should be administered if the serum titer falls
to maintain a serum titer corresponding to a value of at least complete neutralization at a 1:5 serum dilution by the RFFIT.
The frequent-risk category includes other laboratory workers (e.g., those performing rabies diagnostic testing), cavers,
veterinarians and staff, and animal-control and wildlife officers in areas where animal rabies is enzootic. The frequent-risk category
also includes persons who frequently handle bats, regardless of location in the United States or throughout the world, because of
the existence of lyssaviruses on all continents except Antarctica. Persons in the frequent-risk group should have a serum
sample tested for rabies virus neutralizing antibody every 2 years. If the
titer is less than complete neutralization at a 1:5 serum
dilution by the RFFIT, the person also should receive a single booster dose of vaccine. Veterinarians, veterinary students, and
terrestrial
animal-control and wildlife officers working in areas where rabies is uncommon to rare (infrequent exposure group) and
certain at-risk international travelers who have completed a full pre-exposure vaccination series with licensed vaccines and according
to schedule do not require routine serologic verification of detectable antibody titers or routine
pre-exposure booster doses of vaccine. If they are exposed to rabies in the future, they are considered immunologically primed against rabies and simply
require postexposure prophylaxis for a person previously vaccinated (i.e., days 0 and 3 vaccination).

Postexposure Prophylaxis for Previously Vaccinated Persons

If a person is exposed to rabies, local wound care remains an important part of postexposure prophylaxis, even for
previously vaccinated persons. Previously vaccinated persons are those who have received one of the recommended
pre-exposure or postexposure regimens of HDCV, PCECV, or RVA or those who received another vaccine and had a documented rabies
virus neutralizing antibody titer. These persons should receive 2 IM doses (1.0 mL each in the deltoid) of vaccine, one
immediately and one 3 days later. Administration of RIG is unnecessary and should not be administered to previously vaccinated
persons because the administration of passive antibody might inhibit the relative strength or rapidity of an expected anamnestic
response (77). For previously vaccinated persons who are exposed to rabies, determining the rabies virus neutralizing antibody titer
for decision-making about prophylaxis is inappropriate for at least three reasons. First, several days will be required to collect
the serum and determine the test result. Second, no "protective" titer is known. Finally, although
rabies virus neutralizing antibodies are important components, other immune effectors also are operative in disease prevention.

Vaccination and Serologic Testing

Post-Vaccination Serologic Testing

In CDC studies, all healthy persons tested 2--4 weeks after completion of pre-exposure and postexposure rabies prophylaxis
in accordance with ACIP guidelines demonstrated an adequate antibody response to rabies
(18,73,179,180). Therefore, no testing of patients completing pre-exposure or postexposure prophylaxis is necessary to document seroconversion unless the person
is immunosuppressed. Patients who are immunosuppressed by disease or medications should postpone pre-exposure
vaccinations and consider avoiding activities for which rabies pre-exposure prophylaxis is indicated. When that is not possible,
immunosuppressed persons who are at risk for exposure to rabies should be vaccinated and their virus neutralizing antibody titers
checked. In these cases, failures to seroconvert after the third dose should be managed in consultation with appropriate public
health officials. When titers are obtained, specimens collected
1--2 weeks after pre-exposure or postexposure prophylaxis should
completely neutralize challenge virus at a 1:5 serum dilution by the RFFIT. Antibody titers might decline over time since the
last vaccination. Small differences (i.e., within one dilution of sera) in the reported values of rabies virus neutralizing antibody
titer (most properly reported according to a standard as IU/mL) might occur among laboratories that provide antibody
determination using the recommended RFFIT. Rabies antibody titer determination tests that are not approved by FDA are not
appropriate for use as a substitute for RFFIT in suspect human rabies antemortem testing
because discrepant results between such tests and measures of actual virus neutralizing activity by RFFIT have been observed
(181).

Serologic Response and Pre-Exposure Booster Doses of Vaccine

Although virus neutralizing antibody levels might not
definitively determine a person's susceptibility or protection from
a rabies virus exposure, titers in persons at risk for exposure are used to monitor the relative rabies immune status over time
(182). To ensure the presence of a primed immune response over time among persons at higher than normal risk for exposure,
titers should be checked periodically, with booster doses administered only as needed. Two years after primary pre-exposure
vaccination, a complete neutralization of challenge virus at a dilution of 1:5 (by the RFFIT) was observed among 93%--98% of
persons who received the 3-dose pre-exposure series intramuscularly and 83%--95% of persons who received the 3-dose series
intradermally (68). If the titer falls below the minimum acceptable antibody level of complete neutralization at a serum dilution of
1:5, a single pre-exposure booster dose of vaccine is recommended for persons at continuous or frequent risk for exposure to
rabies (Table 6). The following guidelines are recommended for determining when serum testing should be performed after
primary pre-exposure vaccination:

A person in the continuous-risk category should have a serum sample tested for rabies virus neutralizing antibody every
6 months (178).

A person in the frequent-risk category should have a
serum sample tested for rabies virus neutralizing antibody every 2
years (183).

State or local health departments or CDC can provide the names and addresses of laboratories performing appropriate
rabies virus neutralizing serologic testing.

Management and Reporting of Adverse Reactions to Rabies Biologics

Once initiated, rabies prophylaxis should not be interrupted or discontinued because of local or mild systemic adverse
reactions to rabies vaccine. Usually, such reactions can be successfully managed with anti-inflammatory, antihistaminic, and
antipyretic agents.

When a person with a history of hypersensitivity to rabies vaccine must be revaccinated, empiric intervention such as
pretreatment with antihistamines might be considered. Epinephrine should be readily available to counteract anaphylactic
reactions, and the person should be observed carefully immediately after vaccination
(184).

Although serious systemic, anaphylactic, or neuroparalytic reactions are rare during and after the administration of
rabies vaccines, such reactions pose a serious dilemma for the patient and the attending physician
(14). A patient's risk for acquiring rabies
must be carefully considered before deciding to discontinue vaccination. Advice and assistance on the management of serious
adverse reactions for persons receiving rabies vaccines can be sought from the state or local health department or CDC.

All clinically significant adverse events occurring following administration of rabies vaccine should be reported to
VAERS, even if causal relation to vaccination is not certain. Although VAERS is subject to limitations common to passive
surveillance systems, including underreporting and
reporting bias, it is a valuable tool for characterizing the safety profile of vaccines
and identifying risk factors for rare serious adverse reactions to vaccines
(94). VAERS reporting forms and information are
available at http://www.vaers.hhs.gov or by telephone (800-822-7967). Web-based reporting is
available and health-care providers are encouraged to report electronically at
https://secure.vaers.org/VaersDataEntryintro.htm. Clinically significant adverse events
following HRIG administration should be reported to the Food and Drug Administration's MedWatch. Reports can be
submitted electronically to http://www.fda.gov/MedWatch.

Precautions and Contraindications

Immunosuppression

Corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses can interfere with the
development of active immunity after vaccination
(185,186). For persons with immunosuppression,
pre-exposure prophylaxis should be administered with the awareness that the immune response might be inadequate. Patients who are
immunosuppressed by disease or medications should postpone pre-exposure vaccinations and consider avoiding activities for which rabies
pre-exposure prophylaxis is indicated. When this course is not possible, immunosuppressed persons who are at risk for rabies
should have their virus neutralizing antibody titers checked after completing the pre-exposure series. A patient who fails to seroconvert
after the third dose should be managed in consultation with their physician and appropriate public health officials. No cases of
rabies postexposure prophylaxis failure have been documented among persons immunosuppressed because of human
immunodeficiency virus infection.

Immunosuppressive agents should not be administered during postexposure prophylaxis unless essential for the treatment
of other conditions. When postexposure prophylaxis is administered to an immunosuppressed person, one or more serum
samples should be tested for rabies virus neutralizing antibody to ensure that an acceptable antibody response has developed. If
no acceptable antibody response is detected, the patient should be managed in consultation with their physician and
appropriate public health officials.

Pregnancy

Because of the potential consequences of inadequately managed rabies exposure, pregnancy is not considered a
contraindication to postexposure prophylaxis. Certain studies have indicated no increased incidence of abortion, premature births, or
fetal abnormalities associated with rabies vaccination
(187--189). If the risk for exposure to rabies is substantial,
pre-exposure prophylaxis also might be indicated during pregnancy. Rabies exposure or the diagnosis of rabies in the mother should not
be regarded as reasons to terminate the pregnancy
(157).

Allergies

Persons who have a history of serious hypersensitivity to components of rabies vaccine or to other vaccines with
components that are also present in rabies vaccine should be
revaccinated with caution (184).

Indigent Patient Programs

Both rabies vaccine manufacturers have patient assistant programs that provide medications to uninsured or
underinsured patients. Sanofi pasteur's Indigent Patient Program (providing
Imogam® Rabies-HT and
Imovax® Rabies) is administered through the National Organization for Rare Disorders. Information is available by telephone (877-798-8716) or
e-mail (nnadiq@rarediseases.org). Information on Novartis Pharmaceuticals Patient Assistance Program for
RabAvert® is available at
http://www.corporatecitizenship.novartis.com/patients/drug-pricing/assistance-programs.shtml.

Treatment of Human Rabies

Rabies is associated with the highest case fatality rate of any infectious disease. No proven effective medical treatment
is recognized after the development of clinical signs. Combined with intensive care, experimental measures have
included administration of vidarabine, multisite ID vaccination with cell-culture vaccines, human leukocyte interferon, RIG by
the intravenous and intrathecal routes, antithymocyte globulin, inosine pranobex, ribavirin, ketamine, and high doses of
steroids (190--197). Initiation of rabies vaccination after onset of clinical symptoms in patients with confirmed rabies diagnoses is
not recommended and might be detrimental.

Survival has been well documented for only six patients. In five of these cases, the persons had received rabies
vaccination before the onset of disease
(198--202). Only one patient has recovered from rabies without the institution of rabies
vaccination (9,203). Despite these successes, rabies is not considered curable. Treatment of clinical rabies remains an extreme
challenge. Rapid antemortem diagnosis is a priority. When a definitive diagnosis is obtained, primary health considerations should
focus, at a minimum, on comfort care and adequate sedation of the patient in an appropriate medical facility.
Sedation is often necessary because patients might become extremely agitated, especially in the presence of stimuli such as loud noises, air
currents, and the sight or sound of running water, particularly during the acute neurologic phase of the disease
(25). Beyond the overt clinical situation associated with progressive encephalitis, during fluctuating periods of lucidity, patient stress might
be compounded by the psychological trauma resulting from a sense of personal isolation and hopelessness from the prognosis.
As new potential treatments become available, medical staff at specialized tertiary care hospitals might consider institution of
an aggressive approach to experimental therapies, especially in confirmed cases in young healthy persons at an early stage of
clinical disease, after in depth discussions and informed consent by the patient, family or legal representatives
(http://www.mcw.edu/display/router.asp?DocID=11655). Parties authorized to give permission for such treatment also should be aware of the
high probability for treatment failure, the anticipated expenses, and that in the rare instances of patient survival, the recovery
might be associated with a variety of neurologic deficits requiring a lengthy period of rehabilitation
(204). Continued efforts focusing on the elimination of exposure to sources of virus and the institution of
appropriate and timely prophylaxis after exposure
occurs remain the most effective public health measures to prevent human
rabies.

Precautions for Safe Clinical Management of Human Rabies Patients

Human rabies patients do not pose any greater infection risk to health-care personnel than do patients with more
common bacterial and viral infections (25). Medical staff should adhere to standard precautions as outlined by the Hospital
Infection Control Practices Advisory Committee
(126). Staff should wear gowns, goggles, masks, and gloves, particularly during
intubation and suctioning (25). Postexposure prophylaxis is indicated only when the patient has bitten another person or when
the patient's saliva or other potentially infectious material such as neural tissue has contaminated an open wound or mucous
membrane.

Eng TR, Fishbein DB. Epidemiologic factors, clinical findings, and vaccination status of rabies in cats and dogs in the United States in 1988.
National Study Group on Rabies. J Am Vet Med Assoc 1990;197:201--9.

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